DESCRIPTION: (Principal Investigator's Abstract) Scientists from the Fujisawa Pharmaceutical Company recently described the structure, relative stereochemistry, and pronounced cytotoxicity of WS9885B, a bacterial-derived natural product possessing an unprecedented hexacyclic architecture, a reactive bridgehead alkene, and 12 stereocenters. Against several cancer cell lines in vitro, WS9885B displays cytotoxicity as potent as paclitaxel (Taxol), an established drug for the treatment of ovarian and breast cancers. Like paclitaxel, WS9885B stabilizes cellular microtubules in vitro and warrants serious attention as a potential chemotherapeutic agent for the treatment of cancer. WS9885B combines the important elements of novel structure and high biological activity, and is thus an attractive objective for research in organic synthesis. This research proposal describes a hypothetical biogenesis and a novel strategy to achieve an enantioselective chemical synthesis of WS9885B from abundant and inexpensive starting materials. The proposed research seeks to challenge the hypothesis that the architecturally and stereochemically complex structure of WS9885B could evolve from a substantially less complex substance by spontaneous intramolecular reorganization. An enantioselective chemical synthesis of WS9885B would establish its absolute stereochemistry and permit a systematic study of the relationship between its constitution and microtubule-stabilizing properties and cytotoxicity. Long term goals of this research include: (1) to determine if the reactive bridgehead alkene of WS9885B causes covalent modification of microtubules or other cellular components; and (2) the employment of chemistry developed in the course of a total synthesis of WS9885B in syntheses of analogue structures in an effort to define a structure-activity profile for this fascinating cytotoxic natural product.